Genetic and epigenetic risk markers for lung cancer in former smokers

摘要 虽然戒烟努力导致了吸烟和肺癌发病率的下降，但肺癌 仍然是第二种最常见的癌症，也是男性和女性癌症相关死亡的主要原因 女人。目前，在美国新发生的肺癌病例中，至少有一半是前吸烟者。此外， 与吸烟相关的肺癌风险存在种族/民族差异；然而，这些差异的程度尚不清楚。 戒烟后，差异依然存在。肺癌的低剂量CT筛查已被证明可以减少 肺癌死亡率降低约20%；然而，筛查建议仅限于当前吸烟者和最近 戒烟者(15年内)中度或重度吸烟者(≥20包年吸烟史)，这是 没有考虑戒烟15年和/或轻度吸烟者的风险。先前的遗传，表观遗传， 分子标记研究表明，这些标记的频率或水平的差异可能 有助于更好地了解不同人群之间的风险差异。我们的数据表明，吸烟可能与 影响整个种群的DNA甲基化水平，以及遗传、表观遗传和生化标记 在独立于自我报告的多民族人群中，吸烟可能与肺癌风险有关 吸烟数据。这项建议的目的是提高对肺癌发病机制的了解。 前吸烟者人群中的风险。我们建议评估戒烟对肺癌风险的影响。 来自多民族队列研究(MEC)的五个种族/民族群体的疾病风险不同(目标1)。 我们将在前吸烟者中进行一项表观基因组范围的关联研究(Ewas)。 MEC(目标2)。最后，我们将系统地研究遗传变异和DNA甲基化之间的关系 从血白细胞和尿镉水平(目标3)与肺癌风险。此外，我们还将互动 与P01中的其他三个项目一起研究CYP2A6基因变异对年份的影响 QUIT(项目2)、遗传变异与曝光组标记的关联(项目3)和关联 用AHRR的DNA甲基化测定尿菲代谢物比率(项目4)。我们假设 既往吸烟者患肺癌风险的种族/种族和个体差异部分是由于 遗传学和对戒烟的不同生物学反应。这项研究的发现将扩大我们的 了解多民族前吸烟者患肺癌的风险和潜在机制。 这将有助于识别和筛查那些仍有最高肺癌风险的人。 已经采取了戒烟的主要步骤来降低他们的风险。

ABSTRACT While smoking cessation efforts have resulted in a decrease in smoking and lung cancer rates, lung cancer remains the second most common cancer and the leading cause of cancer-related deaths for both men and women. Currently, at least half of the newly incident lung cancer cases are former smokers in the US. Moreover, there are racial/ethnic differences in smoking-related lung cancer risk; however, it is unclear of the extent these differences persist after smoking cessation. Low-dose CT screening for lung cancer has been shown to reduce lung cancer mortality by ~20%; however, screening recommendations are limited to current smokers and recent quitters (within 15 years) who were moderate or heavy smokers (≥20 pack-year smoking history), which does not address risk among those who have quit >15 years and/or who are light smokers. Prior genetic, epigenetic, and molecular marker studies have shown that differences in the frequencies or levels of these markers, may help to better understand risk differences across populations. Our data suggests that smoking may differentially influence DNA methylation levels across populations and that genetic, epigenetic, and biochemical markers of smoking may be associated with lung cancer risk in a multiethnic population independent of self-reported smoking data. The objective of this proposal is to improve the understanding of the mechanisms of lung cancer risk in a former smoker population. We propose to evaluate the impact of smoking cessation on lung cancer risk across five racial/ethnic groups from the Multiethnic Cohort study (MEC) with disparate risk of disease (Aim 1). We will conduct an epigenome-wide association study (EWAS) of years quit among former smokers from the MEC (Aim 2). Lastly, we will systematically investigate the association of genetic variants and DNA methylation from blood leukocytes and urinary cadmium levels (Aim 3) with risk of lung cancer. Additionally, we will interact with the other three projects in this P01 to study the influence of CYP2A6 genetic variants in relation to years quit (Project 2), the association of genetic variants with markers of the exposome (Project 3) and the association for urinary phenanthrene metabolite ratio with DNA methylation of AHRR (Project 4). We hypothesize that ethnic/racial and individual differences in lung cancer risk in former smokers are in part due to variations in genetics and different biological response to smoking cessation. The findings from this study will expand our understanding of risk and potential mechanisms for lung cancer in a multiethnic population of former smokers. This will help to identify for screening those individuals remaining at greatest risk of lung cancer despite them having taken the major step of quitting smoking to reduce their risk.